Epilepsy, especially temporal lobe epilepsy, is a serious disease which can be of idiopathic or symptomatic origin. Typical treatments include the use of anticonvulsants, such as phenytoin or phenobarbital, to control the characteristic seizures.
The dentate gyrus is a brain region that is critically involved in temporal lobe epilepsy (20). A hallmark of temporal lobe epilepsy is the abnormal organization of mossy fibers, the axons of granule neurons in the dentate gyrus (20). This reorganization of the mossy fiber system is believed to be a major contributor to seizure recurrence in these patients (20). In rats, pilocarpine-induced seizures result in a characteristic sequence of events that ultimately leads to the spontaneous recurrence of seizures several weeks after the initial episode of status epilepticus (12). This experimental method of seizure induction provides an excellent model of temporal lobe epilepsy in humans (12). Recently, it has been speculated that the abnormal mossy fibers produced following pilocarpine-induced seizures originate from granule neurons newly produced in response to the seizures (16). Seizures stimulate the proliferation of granule cell precursors which, in turn, produce abnormal mossy fibers (16). This abnormal mossy fiber production is believed to produce spontaneous recurrent seizures in these animals and thus mimic epilepsy in humans.
In the majority of regions in the mammalian brain, the genesis of neurons is restricted to a discrete time period beginning during gestation and completed within several days. Once this developmental phase ends, neurons differentiate and new neurons cannot be produced. In contrast, the granule cells of the dentate gyrus (part of the hippocampal formation) are formed during an extended period that begins during gestation and continues into adulthood (2, 8).
In adulthood, granule neurons are produced from precursor cells that reside primarily in the subgranular zone, the region between the granule cell layer and hilus (2). It has been demonstrated that these precursor cells proliferate and give rise to immature granule neurons that become incorporated into the granule cell layer and express markers of mature granule neurons, including neuron specific enolase, the calcium binding protein calbindin, and the NMDA receptor subunit NR1, within three weeks of DNA synthesis (4). In addition, these granule neurons produced in adulthood receive synaptic input and extend axons into the mossy fiber pathway (19). The continued production of neurons in the dentate gyrus into adulthood is a common characteristic of most, if not all, mammalian, species, from rodents to primates (2,9).
There have been suggestions that the neurotransmitter serotonin or 5-hydroxytryptamine (5HT) might stimulate the production of granule neurons in the dentate gyrus in adulthood. First, serotonin has been shown to stimulate cell proliferation in many nonneuronal systems (2,5,21). Second, the dentate gyrus is enriched with a specific serotonin receptor subtype (5HT1A) (1) and receives serotonergic innervation from the median raphe nucleus of the brainstem (1). Third, conditions that inhibit granule cell genesis, such as malnutrition (7), high corticosterone (9), stress (9) and NMDA receptor activation, also decrease the density of 5HT fibers or 5HT1A receptors, or inhibit the release of 5HT in the dentate gyrus (3, 14, 15, 22 23). Conversely, experimental manipulations that stimulate granule cell genesis, such as adrenalectomy and NMDA receptor antagonist treatment, also increase the density of 5HT1A receptors or the release of 5HT in the dentate gyrus. (11, 22).
Contrary to the instant invention, compounds which are agonists of the 5HT1A receptor have been suggested as therapeutic agents for the treatment of disease states which exhibit unwanted and abnormal involuntary movements such as those found in epilepsy, parkinsonism, Huntingtons's chorea, tardive dyskinesia, Freidreich's atoxia, presenile dementia, and Gilles de la Tourette's syndrome, see for instance, PCT Published Application WO 93/13766 and PCT Published Application WO 96/04287. These agonists are postulated to inhibit neuronal activity and thus decrease seizure discharge.
In spite of the available therapeutic agents, there remains a need for useful methods of preventing and treating epilepsy in mammalian patients.